Page 41 - Characterization of genetic neurodevelopmental disorders at adult age, with a focus on 22q11.2 deletion syndrome - Emma Boersma

Early infantile
epileptic
encephalopathy 4
(STXBP1)
Glutaric aciduria type
I (GCDH)
Mevalonic aciduria
(MVK) NR4A2 Pyruvate carboxylase
deficiency (PC)
SPG10 (KIF5A) Alexander disease
(GFAP)
BPAN (WDR45) Christianson
syndrome (SLC9A6)
DOORS syndrome
(ATP6V1B2)
JNCL (CLN3) Mucolipidosis type II
(GNPTAB)
NUS1 RAB39B SPG15 (ZFYVE26) Parkinsonism in GNDs
Pathogenic variants in STXBP1 may cause significant impairment of
complex I of the mitochondrial respiratory chain and may disrupt the self-
replicating aggregation of α-synuclein.26
GCDH plays a key role in the catabolism of lysine, hydroxylysine, and
tryptophane. Deficiency of GCDH leads to accumulation of glutaric
acid and 3-hydroxyglutaric acid that can induce neuronal death
through excitotoxicity as well as mitochondrial dysfunction and altered
neurotransmission.27
Pathogenic variants in MVK may result in mitochondrial dysfunction,
impaired cholesterol biosynthesis, toxic basal ganglia mevalonate
accumulation and intracerebral inflammation.28,29
Pathogenic variants in NR4A2 are implicated in development and
survival of dopaminergic neurons in the substantia nigra, and may
lower expression of genes associated with mitochondrial function and
oxidative phosphorylation.30
PC encodes for pyruvate carboxylase, a mitochondrial enzyme that
catalyzes pyruvate to oxaloacetate, intermediates in the Krebbs cycle and
is important for neurotransmitter synthesis.31
Axonal transport defect of mitochondria has been shown in a KIF5A
knockout mouse model.32
2
Autophagic-lysosomal system
GFAP encodes for glial fibrillary acidic protein (GFAP), an intermediate
filament protein in astrocytes. GFAP accumulation has been associated
with autophagy in astrocytic cells.33
Pathogenic variants of WDR45, encoding for WIPI4 protein, may cause
iron accumulation in the basal ganglia by impeding autophagy,34 that may
result in neuroinflammation and swelling of the substantia nigra.
SLC9A6 encodes the endosomal Na+/H+ exchanger 6 and is involved
in endosomal luminal pH and trafficking, synapse development and
plasticity.35 Findings in Slc9a6 knock-out mice were consistent with
endosomal-lysosomal dysfunction.36
ATP6V1B2 encodes a subunit of the lysosomal transmembrane proton
pump. Altered lysosomal pH is associated with chronic changes in
autophagy.37
CLN3 is involved in autophagic-lysosomal function. CLN3 is required for
fusion of autophagosomes to lysosomes.38
Pathogenic variants in GNPTAB, that encodes for GlcNAc-1-
phosphotransferase, may cause lysosomal accumulation of nondegraded
material, leading to neuronal dysfunction.39
Deficiency of NUS1, encoding the Nogo B receptor, may result in lysosomal
defects, most likely caused by lysosomal cholesterol accumulation.40
Ras-related proteins play an essential role in neuronal maintenance,
survival and synapse formation. It has been suggested that RAB39B
plays a role in autophagy of dopaminergic neurons. Loss of function may
impair the clearance of α-synuclein.41, 42
Pathogenic variants of ZFYVE26 encoding spastizin, a protein mediating
autophagic lysosome reformation, are believed to cause abnormal
lysosomal storage.43
39